• SCID-X1 Gene Therapy Trial

    Gene Therapy

    Phone: 617-632-5064  

    Gene Therapy for SCID-X1 Using a Self Inactivating (SIN) Lentiviral Vector

    Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 with Low Dose Targeted Busulfan Conditioning

    X-linked severe combined immunodeficiency (SCID-X) is a rare genetic immunodeficiency affecting boys that prevents a child's bone marrow from producing infection-fighting white blood cells. Boys with SCID-X1 die of opportunistic or community acquired infections by 2 years of life unless treated with definitive cellular therapy. The traditional standard therapy is allogeneic stem cell transplant, which carries risks of graft-versus-host disease and other complications related to using allogeneic cells.

    Clinical trials of gene transfer for SCID-X1 using gammaretroviral vectors to transduce autologous CD34+ bone marrow cells documented the efficacy of gene transfer in SCID, but also led to insertional oncogenesis, i.e. T-cell malignancy caused by gammaretroviral integration near oncogenes. A new, safer self-inactivating (SIN) gammaretroviral vector developed and tested in Boston and elsewhere was also effective, while avoiding insertional oncogenesis to date (Hacein-Bey-Abina, Pai et al, New England Journal of Medicine, 2014).

    We have now designed a novel vector to test in a multi-institutional, international clinical trial, G2SCID. This vector has additional features for safety and efficacy while retaining portions of our successful SIN-gammaretroviral vector. Expression of the therapeutic gene, similar to the SIN-gammaretroviral vector, is regulated by an internal housekeeping gene promoter derived from human elongation factor-1 (EF-1) gene. The transgene has been codon optimized, to enhance expression of IL2RG in each transduced cells. The vector is now a SIN-lentiviral vector, which expected to enhance safety considerably. Finally, this protocol includes low dose Busulfan conditioning in patients, in order to enhance correction of humoral (B cell) immunity.

    The trial and accompanying research studies are funded by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. The vector cost is funded by Orchard Therapeutics Ltd.

    Inclusion Criteria:

    • Diagnosis of SCID-X1 based on immunophenotype and lack of T-cell function (proliferation to PHA is less than 10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG
    • Lack of an HLA identical (A, B, C, DR, DQ) related donor
    • Ages 5 years old or younger
    • Signed informed consent
    • Documentation of willingness to follow up for 15 years post-infusion as currently required by the FDA
    • If the patient has previously undergone allogeneic transplant, lack of donor T-cell engraftment must be documented
    • Must be at least 8 weeks of age by the time of Busulfan administration

    Exclusion Criteria:

    • Patients with an active, therapy-resistant infection
    • Uncontrolled seizure disorder or encephalopathy
    • Known disorder affecting DNA repair
    • Contraindication to stem cell collection or to administration of conditioning medication
    • Evidence of infection with HIV-1
    • Active malignancy other than EBV lymphoproliferative disease
    • Previous allogeneic transplant with cytoreductive conditioning
    • Major (life-threatening) congenital anomalies

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